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The Pharmacology of Calcium and ATP-Dependent Potassium

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The Pharmacology of Calcium and ATP-Dependent Potassium THE PHARMACOLOGY OF CALCHJM AND ATP-DEPENDENT POTASSHJM CHANNELS IN ERYTHROCYTES AND IN SMOOTH AND SKELETAL MUSCLE D. C H. Benton A thesis submitted for the degree of Doctor of Philosophy Department of Pharmacology University College London Gower Street LONDON WCIE 6BT 1995 ProQuest Number: 10044587 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10044587 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Potassium channels are a diverse class of membrane proteins found in virtually all cells. The first part of this study concerns the pharmacology of the calcium activated potassium channel found in mammalian erythrocytes. This channel is blocked by cetiedil, an anti-sickling agent, and the initial section of the thesis explores the structure activity relationship (SAR) of compounds related to cetiedil, investigates their mechanism of action and compares them with other blocking agents. This was studied by measuring the effects of the test compounds on the K^a -mediated net K'*' loss which results from the application of A23187 to a suspension of rabbit erythrocytes. Qualitative differences between the action of the cetiedil analogues and another potent K^a blocker, clotrimazole, were observed, suggesting a different mechanism of channel block. The relative activity of the optical enantiomers of cetiedil, UCL 1348 and UCL 1349, as anti- muscarinic and calcium entry blocking agents were also examined. Finally, the ability of cetiedil and two of its analogues, UCL 1495 and UCL 1285, to inhibit levcromakalim stimulated ^^Rb efflux from rat aorta was compared. The results indicate that the SAR for cetiedil at this site differs from that for in erythrocytes. In the second part the effects of channel openers (KCO's) and metabolic inhibition on K+ channels in skeletal muscle were investigated. In the frog, cromakalim and levcromakalim increased ^^Rb efflux and caused membrane hyperpolarisation associated with a decrease in input resistance. The effects of cromakalim were blocked by glibenclamide and tolbutamide. These findings are consistent with an action of cromakalim on ATP-sensitive potassium channels (Ky^^p) Comparisons are made between this channel and the KCO sensitive K"*" channel of smooth muscle. Levcromakalim was far less effective in mammalian skeletal muscle and possible reasons for the difference between frog and mammalian muscle are discussed. An incidental observation was that metabolic inhibition caused a large Ba^+ sensitive increase in ^^Rb efflux from mouse soleus. However, only a small component was blocked by glibenclamide suggesting involvement of channels other than K^-pp. Acknowledgments I am indebted to Professor D.H. Jenkinson for acting as my supervisor and for his encouragement and unfailing patience. I am also grateful to Dr. D.G. Haylett and Dr. P. M. Dunn who have given me much advice over the years. I would also like to thank Professor C. R. Ganellin for his help on medicinal chemistry and to his team of chemists. Dr. C. Roxburgh, Dr. S. Athmani, Dr. W. Quaglia and Ms Z. Miscony who synthesized the novel compounds used in this study and who have also given me valuable advice. The other members of the channel group have provided constant support as well as productive and lively discussion on all aspects of my work. In particular I would like to thank Mr. M. Shiner and Ms M. Malik with whom I have worked closely on the erythrocyte project. Ms K.S. Burke and Mr. A G. Jones have also been generous in allowing me access to their results. This thesis is dedicated to Georgina and to Eleanor. Publications B e n t o n , D.C.H., a n d H a y let t , D.G. (1990). Cromakalim increases the membrane permeability of frog skeletal muscle in vitro. Br. J. Pharmacol 99; 196P. B e n t o n , D C , a n d H a y let t , D.G. (1992). Effects of cromakalim on the membrane potassium permeability of frog skeletal muscle in vitro. Br. J. Pharmacol 107(1): 152-155. B e n t o n , D.C.H., A t h m a n i , S., Ro x b u r g h , C.J., Sh iner , M A R , H a y let t , D.G., G a n e l l in , C R , a n d Je n k in s o n , D.H. (1994). Effects of cetiedil and its analogues on the Ca-açtivated permeability of rabbit erythrocytes and on levcromakalim-stimulated *^Rb efflux from rat aorta. Br. J. Pharmacol 112:466P. Contents Abstract 2 Acknowledgments 3 Publications 4 List of figures 11 List of tables 14 Section I Introduction 15 1 INTRODUCTION 16 1.1 Diversity of iC channels 16 1 . 1 .1 JC channel nomenclature 19 1.2 Calcium activated channels in erythrocytes 20 1.2.1 The Gardas effect 20 1.2.2 Effects of and other divalent metal ions on the fC permeability o f erythrocytes 20 1.2.3 Calpromotin 22 1.2.4 Biophysical properties of erythrocyte Kca 23 1.2.5 Channel density 25 1.2.6 Pharmacology 25 1.2.6.1 Charybdotoxin 25 1.2.6.2 Dihydropyridines 25 1 .2.6.3 Clotrimazole and other imidazole anti-mycotic agents 27 \.2.6A Quinine 27 1.2.6.5 Carbocyanine dyes 27 1.2.6.6 Bepridil 28 1.2.6.7 Cetiedil 28 1.2.7 Sickle cell anaemia 29 1.3 ATP-Sensitive channels 30 1.3.1 K a t p in skeletal muscle 30 1.3.2 Biophysical properties of KatpIn frog skeletal muscle 31 1.3.1 .2 Effect of A TP and other nucleotides on K a t p 31 1.3.1.3 Regulation of K a t p by pH ^ 32 1.3.1.4 Blockers of K a t p 32 1.3.2 K a t p in smooth muscle 33 1.4 The Pharmacology of Channel Openers 34 1.4.4 Effects of KCO *s in skeletal muscle 36 1.4.2 Smooth Muscle 36 1.4.2 . 1 Mechanism by which KCO's cause relaxation 37 1.4.2.2 Blockers of the effects of KCO's in smooth muscle 37 1.4.2.2.1 Glibenclamide andsulphonylureas 37 1.4.2.2.2 Tedisamil 39 1.4.2.2.3 Ciclazindol 39 1.4.2.2.4 Guanethidine andbretylium 39 1.4.2.2.5 Phentolamine 39 1.4.2.2.6 Toxins 40 1.4.2.3 Target channel of KCO's in vascular smooth muscle 40 1.4.2.3.1 Calcium activated channels 40 1.4.23.2 K a t p 40 1.4.23.3 7%g 'delayed rectifier hypothesis ' 41 1.4.4 Site and Mechanism of action of KCO *s 42 Section II Methods 44 2 MEASUREMENT OF K" LOSS FROM ERYTHROCYTES 45 2.1 Preparation of red blood cells 45 2.2 Preparation of sensitive electrodes 45 2.2.1 Calibration of sensitive electrodes 46 2.3 Measurement of loss initiated by the calcium ionophore A23187 47 2.4 Activation of Kc« by Lead ions 50 2.5 Preparation of buffered calcium solutions 50 2.6 Effect of blocking agents on the release caused by the calcium ionophore A23187 50 3 “RUBroiUM EFTLUX STUDIES WITH SKELETAL AND SMOOTH MUSCLE 51 3.1 Muscle preparations 51 ZA A Frog Skeletal Muscle 51 3.1.2 Mouse Skeletal Muscle 51 3.1.3 Rat Aorta and Annococcygeus 51 3.2 Solutions and experimental conditions 52 3.3 ’Loading' of tissue with ^Rb and preparation of samples 52 3.4 Design of experiments 54 3.4.1 Studies on the action of potassium channel openers on efflux from skeletal muscle 54 3.4.2 ^Rubidium efflux from metabolically inhibited muscle 55 3.4.3 Effects ofpotassium channel openers on ^Rb efflux from smooth muscle 55 4 ELECTROPHYSIOLOGICAL RECORDINGS 57 4.1 Design of experiments 57 4.2 Solutions and recording conditions 57 4.2.1 Frog skeletal muscle 57 4.2.2 Mouse Diaphragm 58 4.3 Equipment 58 5 ACTIVITY OF THE ENANTIOMERS OF CETIEDIL, UCL1348 AND UCLI349 AS ANTI-MUSCARINIC AND CALCIUM ENTRY BLOCKING AGENTS 59 5.1 Calcium entry blocking activity in guinea pig taenia caeci 59 5.1.1 Preparation o f tissue and solutions 59 5.2 Anti-muscarinic activity in guinea pig ileum 59 6 DATA ANALYSIS 61 Section III The effects of cetiedil, quinine, clotrimazole and related compounds on channels in erythrocytes and in smooth muscle 62 7 EFFECTS OF CETIEDIL, QUININE, CLOTRIMAZOLE AND RELATED COMPOUNDS ON THE CALCIUM ACTIVATED POTASSIUM PERMEABILITY OF ERYTHROCYTES 63 7.1 Preliminary work on the SAR of cetiedil - the influence of log P 63 7.2 Piperidine derivatives with alkyl substitutions 69 7.3 Compounds with polar and non polar substitutions at position 4 of the piperidine ring 77 7.4 Congeners of UCL 1495 82 7.5 Quinoline and isoquinoline derivatives 90 7.6 ’Open-ring' derivatives of UCL 1274 94 7.7 9 benzyl 9 flourenyl analogues of cetiedil 94 7.8 Effects of quinine analogues 98 7.9 Effects of imidazole derivatives 103 7.10 Summary 107 8 MECHANISTIC STUDIES OF THE ACTION OF CETIEDIL ANALOGUES AND CLOTRIMAZOLE ON THE CALCIUM ACTIVATED POTASSIUM PERMEABILITY OF ERYTHROCYTES 114 8.1 Do the cetiedil analogues act directly on channels? 114 8.1.1 Effect of UCL 1274 on net K* loss stimulated by A23187 and Pb^ ions 114 8.1.2 Effect of UCL 1274 on the Ca^^ concentration-response curve 117 8.2 Effect of extracellular[K^] on potency of blocking agents 120 8.3 Slope of concentration response curves for UCL 1495 and clotrimazole 120 8.4 Comparison of effects of blocking agents on kinetics of ionophore stimulated loss 121 8.5 Summary 125 9 EFFECTS OF CETIEDIL AND ITS ANALOGUES ON POTASSIUM CHANNEL OPENER-STIMULATED EFFLUX FROM SMOOTH MUSCLE 131 9.1 Effects of potassium channel openers on ^Rb efflux from rat aorta 131 9.2 Effect of cetiedil, UCL 1285 and UCL 1495 126 9.3 Effect of levcromakalim on *^Rb efflux from rat anococcygeus 133
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